Recombinant Human Chorionic Gonadotropin in Supporting Tolerance and Repairs in Patients with High-Risk or Refractory Acute Graft Versus Host Disease
This phase I/II trial studies the side effects and the best dose of recombinant human chorionic gonadotropin and to see how well it works in supporting tolerance and repairs in patients with acute graft-versus-host disease that is high-risk or does not respond to treatment. Recombinant human chorionic gonadotropin may be an effective treatment for graft versus host disease caused by a hematopoietic cell transplant.
Inclusion Criteria
- Acute graft versus host disease (GVHD) fitting one of the following categories:
- High-Risk aGVHD (ARM 1) * Pediatric or adult hematopoietic cell transplant (HCT) recipients with high-risk acute GVHD, as determined by the refined Minnesota Medical (MN) acute GVHD risk score OR high risk on the basis of blood biomarkers (Ann Arbor score 3 or amphiregulin >= 33 pg/ml); patients in this arm must start treatment within the first 7 days after onset of high-risk aGVHD or
- Steroid-Dependent aGVHD (ARM 2A) * Pediatric or adult HCT recipient with grade II-IV steroid-dependent acute GVHD, defined as any one of the following: ** Flare of acute GVHD of at least grade II/IV severity within 8 weeks of tapering down or (off of) immunosuppression for acute GVHD, with the flare occurring on =< 0.5 mg/kg prednisone; this can include late-onset aGVHD and overlap syndrome or
- Steroid-Refractory aGVHD (ARM 2B) * Pediatric or adult HCT recipient with grade II-IV steroid refractory acute GVHD, defined as any one of the following: ** No response of acute GVHD after at least 4 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent ** Progression of acute GVHD within 3 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent ** Failure to improve to at least grade II acute GVHD after 14 days of systemic corticosteroids, with initial doses of at least 2 mg/kg prednisone or equivalent ** Flare of acute GVHD of at least grade II/IV severity while on steroids at a dose > 0.5/mg/kg/day; this can include late-onset aGVHD and overlap syndrome
- Serum creatinine =< 2.5 x upper limit of normal (ULN) (within 7 days)
- Left ventricular ejection fraction (LVEF) >= 35% (within 42 days)
- Voluntary written consent (adult or parent/guardian with minor assent for 12 through 17 year olds)
Exclusion Criteria
- Progressive malignancy
- Diagnosis of a hormone responsive malignancy
- Uncontrolled infection at initiation of protocol treatment
- Current thromboembolic disease requiring full-dose anticoagulation patients receiving pharmacologic prophylaxis for thromboembolic disease will be eligible
- Active or recent (within prior 3 months) thrombus, irrespective of anticoagulation status
- Pregnancy as assessed on baseline blood hCG level
- Unwilling or unable to stop supplemental sex hormone therapy (estrogen, progesterone, and/or testosterone preparations)
- Women or men of childbearing potential unwilling to take adequate precautions to avoid pregnancy from the start of protocol treatment through 28 days after the last treatment
Additional locations may be listed on ClinicalTrials.gov for NCT02525029.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of recombinant human chorionic gonadotropin (Pregnyl) when given with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory acute graft-versus-host disease (aGVHD). (Phase I)
II. To determine the proportions of complete, partial, mixed, and no response among surviving patients at days 28 after initiation of protocol therapy in pediatric and adult patients with high-risk (Arm 1) or refractory (Arm 2) aGVHD. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the safety and feasibility of human chorionic gonadotropin (hCG) supplementation with Pregnyl in combination with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory aGVHD.
II. To determine the incidence of acute GVHD flare after complete response (CR)/partial response (PR) requiring increase of steroids or other systemic treatment at days 28 and 56.
III. To compare the rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.
CORRELATIVE OBJECTIVES:
I. Pharmacokinetics (clearance, half-life, volume of distribution) of the both the hCG and epidermal growth factor (EGF) components of urinary hCG when administered to patients with GVHD.
II. Monitoring for hormonal effects via determination of serum concentrations of hCG, estradiol, progesterone, and testosterone on days 7, 14, 28, and 56, compared to baseline.
III. Collection of blood samples for measurement of immune and tissue damage/repair biomarkers to determine change from pre-treatment levels to levels obtained on days 7, 14, 28, and 56 post-treatment.
IV. Analysis of previously collected skin and/or gastrointestinal biopsies for biomarkers of refractory aGVHD and response to therapy.
TRANSPLANT RELATED OBJECTIVES:
I. To determine the disease-free survival, overall survival, and non-relapse mortality at day 28, 56, 180 and 1 year of protocol treatment.
II. To determine the incidence of chronic GVHD at day 180 and 1 year.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms.
ARM I (HIGH-RISK aGVHD): Patients receive standard of care immunosuppression and recombinant human chorionic gonadotropin subcutaneously (SC) every other day (QOD) for 4 doses. Patients achieving complete or partial response may continue recombinant human chorionic gonadotropin for an additional 5 weeks.
ARM II (STEROID-REFRACTORY/DEPENDENT aGVHD): Patients receive standard of care immunosuppression and recombinant human chorionic gonadotropin SC QOD for 7 doses. Patients achieving a complete or partial response may continue recombinant human chorionic gonadotropin for an additional 5 weeks.
After completion of study treatment, patients are followed up on days 28 and 56 days.
Trial PhasePhase I/II
Trial Typesupportive care
Lead OrganizationUniversity of Minnesota/Masonic Cancer Center
Principal InvestigatorShernan Grace Holtan
- Primary ID2014LS020
- Secondary IDsNCI-2015-02022, MT2014-12
- ClinicalTrials.gov IDNCT02525029